Phthalocyanines (Pc's) and their symmetrically substituted derivatives have received extensive interest in the last decades since their special properties (e.g. electrical conductivity, electrochromism, mesophase formation and aggregation into monolayers of Langmuir-Blodgett type) make them interesting substrates for new materials. Much less is known about the unsymmetrical derivatives of Pc which are expected to maintain additional facilities in areas like photodynamic therapy of cancer (PDT), photoinactivation of viruses in stored blood products and nonlinear optics.
The reason for the limited use of this type of compounds is mostly attributed to the difficulty of isolating the desired products from the statistically condensed mixture of two or more different phthalonitrile (diiminoisoindoline) derivatives. Complexity of such mixtures requires time-consuming chromatographical separation procedures and the yield of the desired products is usually very low. Therefore, efficient synthetic routes to each isomer are required. In this context three methods for the preparation of mono- and disubstituted lipophilic Pc's and their analogs are noteworthy: condensation of an iminoisoindoline derivatives either with 1,3,3-trichloroisoindoline, with another sterically crowded diiminoisoindoline or with 1,3-bis((3'-imino-1'-isoindolinydene)amino)-1,2,4-triazole (or its metal complex). None of these methods have been applied to the synthesis of Pc's featuring hydrophilic substituents, specifically sulfo groups, on the benzo rings. Meanwhile, designing the synthetic ways leading to water soluble and amphiphilic Pc's and their analogs, carrying well defined substituents, remains a challenge. Due to their water solubility and/or ease of formulation, these compounds are particularly sought after as photosensitizers for medical application. Some amphiphilic Pc's, envisioned for this application, such as metal free mono(tert-butyl)trisulfoPc and its zinc complex, could not be obtained using conventional condensation of two different precursors. We have recently reported the method for preparing monosulfonated Pc's and their derivatives via the Meerwein reaction, affording the definite positional isomers without chromatographical separation of polysulfonated mixtures. However, di- and trisulfonated Pc's cannot be obtained using this synthetic route.
There was surprisingly discovered an alternative procedure for the preparation of unsymmetrical Pc's with identical substituents on three of the benzene units and a different substituent on the fourth one. Preorganization of three phthalonitrile units as a subphthalocyanine (SubPc) of boron (III) and subsequent conversion into a Pc macrocycle via reaction with various substituted diiminoisoindolines, has proven to be an efficient way of obtaining unsymmetrical Pc's containing different lipophilic substituents, such as alkyl-, alkoxy-, alkylthio-, nitro- and crown ester groups. To our knowledge, this method was never applied for the preparation of water soluble Pc's, and SubPc's substituted with hydrophilic moieties in benzo rings are not known in the art.
Compared to Pc's, SubPc's--i.e. the lower homologues of Pc composed of three diiminoisoindoline units have traditionally been ignored because of difficulties related to their purification (b,e). Meller and Ossko reported the synthesis of boron(III) SubPc's with an axial halogen, SubPcB(X), where X=F, Cl, already in 1972. In their experiments, SubPc's were formed in the reaction of BF.sub.3, BCl.sub.3 or PhBCl.sub.2 with phthalonitrile in boiling 1-chloronaphthalene. Subsequently it was shown that this procedure results in the formation of many secondary products, consisting of peripherally halogenated products, which complicate separation and purification of the desired products. These secondary reactions concern electrophilic substitution of free halogen, generated from BX.sub.3 (X=F, Cl) or PhBCl.sub.2 with the macrocycle, catalysed by unreacted BX.sub.3.
Formation of unsubstituted and tris(tert-butyl) substituted SubPc's with an axial bromine, SubPcB(Br), was also described. These compounds were obtained by reaction of bromophenylboranes (Ph.sub.2 BBr or PhBBr.sub.2) and appropriate phthalonitrile in 1-chloronaphthalene. However, further attempts to repeat the synthesis of tert-Bu.sub.3 SubPcB(Br) yielded a product, which was identified as tert-Bu.sub.3 SubPcB(Ph) containing an axial phenyl group.
The present invention relates to the synthesis of the bromoboron(III) tri(4-chlorosulfonyl)SubPc 1, hydroxyboron(III) tri(4-sulfo)SubPc tripyridinium salt 2 and hydroxyboron(III) tri(4-alkylsulfamoyl)SubPc or hydroxyboron(III) tri(4-phenylsulfamoyl)SubPc type of 3, which served as precursors for the preparation of a wide range of unsymmetrical metal free Pc's, benzonaphthoporphyrazines (BNP's), and Pc aza-analogs (azaPc's), containing three sulfo- or sulfamoyl groups per molecule (Scheme 1).
Reactions of SubPc's with the diiminoisoindoline derivatives were accomplished at different temperatures depending on the reactivity of the latter compounds, using DMSO or a mixture DMSO--1-chloronaphthalene 2:1 as solvent
Synthesized Pc's and their derivatives were purified by reprecipitation from different solvents depending on the type of substituents and, therefore, solubility.
Further metallation of the metal free compounds with divalent metals was accomplished using appropriate metal salts in methanol and/or DMF. ##STR1##
Varying substituents on the benzo rings of diiminoisoindoline allows for fine tuning of the long-wave absorption maxima of Pc's. Increasing the lipophilic part of the molecule which always contains three sulfo groups on its hydrophilic part, e.g. series 14, 15 (Group 1, Scheme 2), 29, 32 (Group 2, Scheme 3) or 42, 44-46 (Group 3, Scheme 4), and introducing additional N-atoms into the benzo rings of Pc's (Group 3) allows for control of the solubility of the resulting complexes in a vast range of organic solvents and in water at different pH values.
Therefore, the sulfonated derivatives of boron(II) SubPc 1-3 present the universal synthones for preparing unsymmetrical Pc's and their analogs which absorb in the range 600-800 nm (principal absorption maximum) and which possess different solubility--from water soluble through amphiphilic to lipophilic.
Water soluble and amphiphilic Pc's, BNP's and azaPc's 4-5 (Scheme 2), 28-32 (Scheme 3), and 38-46 (Scheme 4), prepared by reaction of 2 with various diiminoisoindolines, can be used as photosensitizing agents in PDT of cancer, for inactivation of viruses in stored blood products, and as materials for gas sensors.
The lipophilic derivatives 16-17 (Scheme 2), 33-37 (Scheme 3), 47-55 (Scheme 4), synthesized from sulfamoyl substituted SubPc's type of 3, can be useful as materials for organic semiconductors and disk memory. ##STR2##